A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies.
Authors: Curtis Andrew Lachowiez, Jacqueline Suen Garcia, Gautam Borthakur, Sanam Loghavi, Zhihong Zeng, George Dono Tippett, Tapan M. Kadia, Lucia Masarova, Musa Yilmaz, Abhishek Maiti, Prithviraj Bose, Koichi Takahashi, Elias Jabbour, Farhad Ravandi, Naval Guastad Daver, Guillermo Garcia-Manero, Paresh Vyas, Hagop M. Kantarjian, Marina Konopleva, Courtney Denton Dinardo
Journal: Journal of Clinical Oncology (2022)

7018 Background: Isocitrate dehydrogenase-1 mutations ( IDH1 + ) result in production of the oncometabolite 2-hydroxyglutarate, arrested differentiation, and increased dependence on the anti-apoptotic protein BCL-2, enhancing susceptibility to the BCL-2 inhibitor venetoclax (VEN). Herein, we report the completed P1b portion of the P1b/II study combining the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continous) with VEN (D1-14), with or without azacitidine (AZA; 75mg/m 2 D1-7 every 28 days). Methods: Eligible patients age 18 with IDH1 + MDS, newly diagnosed (ND: de novo and secondary/treated secondary AML) or relapsed/refractory (R/R) AML were enrolled into 4 dose levels (DL): DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Primary objectives included safety and tolerability, and IWG defined overall response (ORR: CR+CRi+CRh+PR+ MLFS). Results: 31 patients (DL1: 6, DL2: 6, DL3: 13, DL4: 6) enrolled with a median follow-up of 26 months. Median age was 67 years (range: 44-84). 71% had AML (ND: N = 14, R/R: N = 8), 29% (N = 9) had MDS. ELN risk was intermediate and adverse in 19% (N = 6) and 55% (N = 17). Median baseline IDH1 + VAF was 23% (5%-48%). Median time on study was 6.4 (range: 4 -not reached [NR]) months. The ORR was 94% (DL1: 67%, DL2-DL4: 100%); Composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). 63% of AML patients attained measurable residual disease negative CRc by multiparameter flow cytometry (ND-AML: 64%, R/R-AML: 60%). Addition of AZA increased MRD clearance in ND-AML compared to the doublet regimen (86% vs. 25%, p: 0.09). IDH1 + mutation clearance by digital droplet PCR (sensitivity: 0.1-0.25%) was attained in 67% of patients (ND-AML: 83%, R/R-AML: 50%, MDS: 50%) following cycle 5. 35% of patients required dose reductions for cytopenias (DL2: 2 [33%], DL3: 6 [46%], DL4: 3 [50%]). Grade 3-5 adverse events (AEs) occurring in 10% of patients included febrile neutropenia (29%; one episode resulted in death in a R/R-AML patient relapsing on study) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in two patients (dose-limiting toxicity in one), and differentiation syndrome in 4 (G2: N = 2, G3: N = 2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months. 24-month OS was 71% (95% CI: 55-91; [ND-AML: 67%, R/R-AML: 50%, MDS: 100%]). MRD-negative CRc improved OS (median NR vs. 8 months, p: 0.002) in ND and R/R-AML. 100% of patients (N = 4) relapsing after IDH1 + clearance demonstrated no IDH1 + at relapse. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN +/- AZA is an effective treatment for IDH1 + myeloid malignancies with an expected toxicity profile and notable efficacy across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented. Phase 2 enrollment is ongoing. Clinical trial information: NCT03471260.